6-Halo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines

ABSTRACT

7,8-Dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines having a halo substituent at the 6-position have potent dopaminergic activity. The 6-chloro congeners are most active.

This application is a continuation-in-part application of copending Ser.No. 742,965 filed Nov. 17, 1976, now U.S. Pat. No. 4,160,765 issued July10, 1979.

This invention offers a new group of compounds which are1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines having at least threesubstituents in the benz-ring of the nucleus, one of which is a halo orhalo-containing group substituted at the 6-position and the other two,7,8-dihydroxy groups. These dopamine agonists have utility asmedicinally active compounds especially as cardiovascular and/ordiuretic agents due in part to their peripheral dopaminergic activity oras anti-Parkinsonism agents by means of activity at the central dopaminereceptors. Generally speaking therefore they have either potentperipheral or central dopaminergic activity.

STATEMENT OF THE PRIOR ART

Certain 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines have beendescribed in U.S. Pat. Nos. 3,393,192, 3,609,138, 3,743,731, 4,052,506and 4,011,319; British Pat. No. 1,118,688; and Swiss Pat. No. 555,831,including general methods of preparation. However these referencesdisclose no specific benz-trisubstituted compounds, no6-halo-substituted compounds of any kind and no particular advantage to6-halo substitution in the structures. British Pat. No. 1,225,053discloses certain halo-substituted benzazepines not related in structureto those claimed here.

DISCLOSURE OF THE INVENTION

The structures of the compounds of this invention are specificallyidentified by having a halo, that is, a chloro, bromo, iodo or fluoro orhalo-containing substituent such as a trifluoromethyl or trifluoro ethylgroup at the 6-position of the7,8-dihydroxy-1-phenyltetrahydro-1H-3-benzazepine system. Exemplary ofthis new group of compounds are those represented by the followingstructural formulas: ##STR1## in which: R is hydrogen, furylmethyl orthienylmethyl;

R₁ is halo, especially chloro, fluoro or bromo, or trifluoromethyl;

R₂ and R₃ are each hydrogen or a group derived therefrom such as loweralkanoyl of 2-7 carbons for example acetyl, propionyl, isobutyryl,valeryl etc; and

R₄ is hydrogen or from 1 to 3 common phenyl substituents such astrifluoromethyl, halo such as chloro, fluoro or bromo, methyl, methoxyor when substituted with another substituent other than hydrogen,hydroxy or acetoxy.

R₂ O and R₃ O are preferably hydroxy radicals at the 7,8 positions formaximal biological activity.

A subgeneric group of compounds within the above illustrative genericgroup are those of Formula I in which R is hydrogen; R₂ and R₃ are thesame and are hydrogen, isobutyryl or acetyl; and R₄ is hydrogen.

Individual compounds of note are those of Formula II ##STR2## in whichR₁ is chloro or bromo and R₂ and R₃ are the same and are hydrogen oracetyl.

The pharmaceutically acceptable acid addition salts having the utilityof the free bases of formula I, prepared by methods well known to theart, are formed with both inorganic or organic acids, for example:maleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicyclic, methanesulfonic ethanedisulfonic, acetic,oxalic, propionic, tartaric, salicylic, citric, gluconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, hydrochloric, hydrobromic, sulfuric,cyclohexylsulfamic, phosphoric and nitric acids. The hydrohalides ormethane sulfonates are preferred.

It will be obvious to one skilled in the art that the compounds ofFormula I may be present as diastereoisomers which may be resolved intod, l optical isomers. Resolution of the optical isomers may beconveniently accomplished by fractional crystallization of their saltswith optically active acids from appropriate solvents. Specific methodsof resolution are disclosed in Swiss Pat. No. 555,831. Unless otherwisespecified herein or in the claims, it is intended to include allisomers, whether separated or mixtures thereof. Where isomers areseparated, the desired pharmacological activity will usually predominatein one of the isomers.

The compounds of Formula I in which R is hydrogen are generally preparedfrom intermediates of the following formula: ##STR3## in which X ishydroxyl or its functional equivalent, Y is H₂ or ═O, R is hydrogen or achemically inert substituent as defined above, R₁ is halo ortrifluoromethyl; R₂ and R₃ are lower alkyl benzyl or together aremethylene or ethylene; and R₄ is hydrogen or one or more chemicallyinert substituents of the group described above, by means of anintramolecular cyclization effected by reaction with a cyclizing agentsuch as a strong acid for example sulfuric acid, the preferred sulfuricacid in trifluoroacetic acid, polyphosphoric acid, polyphosphoric ester,methanesulfonic acid in methylene chloride or hydrobromic acid or aLewis acid such as boron trifluoride, aluminum chloride or stannicchloride which generates the desired carbonium ion from the substituentX. The term "chemically inert" means under the conditions of thecyclization reaction the substituent is not altered unless of course theoperator so desires. For example carrying out the cyclization in 48%hydrobromic acid when R₂ or R₃ are methyl splits the ether links to givethe desired hydroxy cyclic compounds.

The phenethylamines (IV) which are used as starting materials for thismethod are either known or are prepared by methods described in U.S.Pat. No. 3,211,792, Chem. Abst. 80,95398, U.S. Pat. No. 3,869,474, U.S.Pat. No. 3,804,839, J. Am. Chem. Soc., 78, 4419 (1956) or in theillustrative examples here disclosed.

Alternatively, the compounds of Formula I especially where R is hydrogenmay be prepared from 1-phenyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepineintermediates which are obtained by heating an appropriatephenylalkylamine with an ester of mandelic acid to give the amide ofFormula III where Y is ═O. The latter is then cyclized as describedabove to from the 2-oxobenzazepine intermediates which are chemicallyreduced by standard amide reducing agents, for example with borane,diborane, lithium aluminum hydride, sodium borohydride and propionicacid, diisobutyl aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride, to the 1-phenyl-3-benzazepine products.

The compounds in which R₁ is bromo and R₂, R₃, R₄ and R contain onlychemically inert groups can surprisingly be prepared by directbromination at the 6-position of their chemical structures in excellentyields. This reaction is carried out most conveniently using about twomole equivalents of bromine in a suitable solvent such as acetic acid atabout room or ambient temperature. The yield of the product in which R₁is bromo, R₂ O- and R₃ O- are 7,8-dimethoxy and R and R₁ are hydrogen is70-85%. The product separates from the bromination mixture as a complexwith one mole of bromine. The complexed bromine is eliminated easily bytreatment with methanol/acetone.

The 6-bromo containing compound may optionally serve as an intermediatein a number of ways such as for preparing the 6-chloro, trifluoromethylor iodo congeners. The 6-bromo compound is also useful for preparing6-lithium or Grignard intermediates. These can be reacted with a numberof conventional reactants to introduce 6-substituents such as withiodine, halogenating agents, i.e. hexachloroethane, chlorine,N-chlorosuccinimide and others to introduce halo substituents. In effectthis is a halogen halogen interchange via a metal substituent. Thelithium salts and bromination process are part of this invention claimedelsewhere.

To prepare the compounds of Formula I where R₁ or R₂ is alkanoyl, thecorresponding 3-benzyl-dihydroxy-3-benzazepine (obtained by N-alkylationof the hydroxybenzazepine with benzyl bromide in the presence ofpotassium carbonate) is treated with the appropriate alkanoic acidanhydride or chloride, for example acetic anhydride, and the resultingalkanoyloxy substituted benzazepine is then hydrogenated in the presenceof palladium-on-carbon to remove the protective benzyl group. Thedialkanoyloxy derivatives such as the important 7,8-diacetoxy compoundscan also be prepared by direct O-acylation of the7-halo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide in trifluoroacetic acid at ambient temperature with theanhydride or halide.

The intermediates of Formula III above are conveniently prepared byheating equimolar amounts of a styrene oxide with a2-halo-3,4-dialkoxyphenethylamine which is either known or prepared bymethods known to the art, each appropriately substituted, either aloneor in an inert organic solvent such as tetrahydrofuran. Preferably theheating is effected on a steam bath or at reflux temperature for from 12to 24 hours. The required styrene oxide is conveniently prepared byreaction of the ylide derivative from sodium hydride andtrimethylsulfonium iodide with the appropriately substitutedbenzaldehyde.

Alternatively the phenethanolamine intermediates are prepared bycondensing the 2-halo-3,4-dialkoxyphenethylamines with a blocked orhindered phenylhalohydrin such as: ##STR4## in which X is a blockinggroup known to the art such as tert. butyl.

The active dopaminergic compounds of this invention which stimulateperipheral dopamine receptors, for example, increase renal blood flowand have as an end result antihypertensive activity. This renalvasodilator activity of the benzazepine compounds of Formula I isconveniently measured in an anesthetized dog (see U.S. Pat. No.4,011,319). In this pharmacological procedure, a test compound isadministered at progressively increasing (3-fold) infusion ratesbeginning at 0.1 mcg/kg/min up to 810 mcg/kg/min for 5 minutes each toanesthetized normotensive dogs and the following parameters aremeasured: renal artery blood flow, iliac artery blood flow, arterialblood pressure and heart rate. Results are reported as a percent change,increase or decrease, at time of peak response (from pre-drug controls),and for a significant effect renal blood flow (increase) and renalvascular resistance (decrease) should be approximately 10% or greater.The effect on renal vascular resistance can be calculated from anychange in renal blood flow and arterial blood pressure. To confirm themechanism of action, representative active renal vasodilator compoundsare checked for blockade by bulbocapnine which is known to be a specificblocker of renal dopamine receptors. Representative advantageouscompounds of Formula I,7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine substitutedat the 6-position by chloro or bromo, tested by i.v. infusion asdescribed above produced an ED₁₅ of 3.5 and 22 (9) mcg/kg respectivelywith little direct effect on systemic blood pressure in normotensiveanimals. ED₁₅ therefore is the cumulative dose by infusion whichproduces a 15% decrease in renal vascular resistance ##EQU1## As a renalvasodilator in the anesthetized dog this 6-chloro compound was 10 timesmore efficacious than its 6-deschloro congener.

The compounds of this invention unexpectedly also cause a separation ofside effects in dogs such as those caused by pressor reactions due tonorepinephrine compared with the ED₁₅ cardiovascular dose as describedabove. Here the above 6-chloro and 6-bromo-7,8-dihydroxy compounds havea separation ratio of 1233 and >1388 respectively compared with theirdeshalo congener (47).

In addition to the renal vasodilator activity via a dopaminergic effect,certain benzazepine compounds of Formula I produce weak diureticactivity. Such diuretic activity is measured in the standardsaline-loaded rat procedure. A test compound is administered i.p. atdoses of from 10 to 40 mg/kg and the parameters measured are urinevolume (hourly for three hours) plus sodium and potassium ionconcentrations. Also conventional diuretic tests in the dog may be used.6-Chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinetested in the phosphate mannitol dog produced a significant increase inrenal plasma flow and natriuresis at a dose as low as 5 and 10micrograms, μg/kg/min i.v. Similar results were obtained at oral dosesof 10 mg/kg (renal blood flow only). The 6-chloro-7,8-diacetoxy congenerhas better activity after oral absorption than does its 7,8-dihydroxyparent.

The benzazepine compounds of Formula I also may have antiparkinsonismactivity due to central dopaminergic activity. This CNS activity ofcourse is only possible if the compound crosses the blood-brain barrierfollowing peripheral administration and is thus available at the centraldopamine receptor sites. Such central activity is demonstrated byemploying a modified standard animal pharmacological test procedurereported by Ungerstedt et al., in Brain Research 24, 1970, 485-493. Thisprocedure (see U.S. Pat. No. 4,052,506) is based on a drug inducedrotation of rats having extensive unilateral lesions of the substantianigra. Briefly, the test comprises the quantitative recording ofrotational behavior in rats in which 6-hydroxydopamine lesions of thenigrostriatal dopamine system have been produced. A unilateral brainlesion in the left substantia nigra causes the dopamine receptor in theleft caudate to become hypersensitive following the resultingdegeneration of the nigral cell bodies. These lesions destroy the sourceof the neurotransmitter dopamine in the caudate but leave the caudatecell bodies and their dopamine receptors intact. Activation of thesereceptors by drugs which produce contralateral rotation, with respect tothe lesioned side of the brain, is used as a measure of centraldopaminergic activity of the drug.

Compounds which are known to be clinically effective in controllingparkinsonism, such as, for example, L-dopa and apomorphine, are alsoeffective in this rat turning model. These compounds directly activatethe dopamine receptors and cause contralateral rotation of the lesionedrat.

Rotational activity is defined as the ability of a compound to produce500 contralateral rotations during a two-hour period afteradministration, usually intraperitoneally. The dose corresponding to 500contralateral rotations per two hours is obtained and assigned as theRD₅₀₀ value.

Once again advantageous compounds of Formula I, 6-chloro or6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3benzazepines whentested as described above in rats produced ED₅₀₀, i.p. of 0.3 and 0.27mg/kg respectively. Further the compounds do not induce emesis orstereotyped behavior at doses which are effective in the rat turningmodel.

The same 6-bromo compound showed greater renal plasma flow (RPF) in therat renal clearance test than did the desbromo congener. At 15 μg/kg/minthe RPF increased 60% over control with a 85% increase in urine volume.The 6-chloro compound also increased volume 80%, RPF 48% and sodium ionexcretion. Therefore these compounds demonstrate stronger diureticproperties than does their 6-hydrogen congener.

As mentioned above the 6-halo substitutents but not especially the6-trifluoromethyl substituent unexpectedly increase the potency of thedopaminergic activity of each respective deshalo compound of the priorart. Such an increase in potency is important in reducing the cost ofmedication or in decreasing the side effect liability of the compoundwhich may be present at higher doses. Following is a tabular compilationof the results of testing, in the two basic screening models forperipheral (ED₁₅) or central (RD₅₀₀) dopaminergic activity, selectedbasic compounds of the series claimed here compared with the compoundshaving the closest structure in the prior art or with compounds havingstructures even closer to those claimed. It should be emphasized that wehave much more biological data than that presented here but that thefollowing data was selected to demonstrate the unexpected biologicalactivity due to the specific 6-halo-7,8-hydroxy substitution system inthe 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine series represented byFormula I:

                  TABLE I                                                         ______________________________________                                        No.  Salt   R     R.sub.1                                                                            R.sub.2                                                                             R.sub.3                                                                           R.sub.4                                                                           ED.sub.15 *                                                                         RD.sub.500 **                      ______________________________________                                        1.   HBr    H     H    H     H   H   80 (3)                                                                              --                                                                      35 (3)                                                                              --                                      HCl    H     H    H     H   H   31 (3)                                                                              0.22                               2.   HBr    H     OH   H     H   H   ina. (2)                                                                            ina.                               3.   HCl    H     9-Cl H     H   H   ina. (1)                                                                            10 (547 ± 215)                  4.   HBr    H     Cl   9-OH  H   H   4500  ina.                                                                    (2)                                      5.   HBr    H     Cl   H     H   H   3.5 (2)                                                                             0.3                                6.   HBr    H     Br   H     H   H   9 (3) 0.27                               7.   HBr    H     F    H     H   H   9 (3) 4.9 (p.o.)                         ______________________________________                                         *ED.sub.15 in mcg/kg. i.v.; with the number of dogs in the test.              **RD.sub.500 mg/kg. i.p.; if an RD.sub.500 was not obtained the number of     rotations and deviation at a certain dose are present unless the figure i     insignificant.                                                           

From this data, it is evident that compounds 5-7 have 4 to 10 times theED₁₅ of the closest prior art compound described as a dopaminergic agent(compound 1). Also moving the halo to position 9 (compound 3) reducesthe dopaminergic activity almost to nil as does moving the 7-hydroxygroup to position 9 (compound 4). Both of these compounds (compounds 3and 4) are position isomers of those claimed here.

The pharmaceutical compositions of this invention having dopaminergicactivity are prepared in conventional dosage unit forms by incorporatinga compound of Formula I, an isomer or a pharmaceutically acceptable acidaddition salt thereof, with a nontoxic pharmaceutical carrier accordingto accepted procedures in a nontoxic amount sufficient to produce thedesired pharmacodynamic activity in a subject, animal or human.Preferably the compositions will contain the active ingredient in anactive but nontoxic amount selected from about 15 mg to about 1000 mg ofactive ingredient per dosage unit but this quantity depends on thespecific biological activity desired and the conditions of the patient.Generally speaking lower doses are needed to stimulate central dopaminereceptors than peripheral receptors.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid,and the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly the carrier or diluent may includeany time delay material well known to the art, such as glycerylmonostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier for oral administration is used the preparation can be tableted,placed in a hard gelatin capsule in powder or pellet form, or in theform of a troche or lozenge. The amount of solid carrier will varywidely but preferably will be from about 25 mg to about 1 g. If a liquidcarrier is used, the preparation will be in the form of a syrup,emulsion, soft gelatin capsule, sterile injectable liquid such as anampul, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following the conventionaltechniques of the pharmaceutical chemist involving mixing, granulatingand compressing when necessary, or variously mixing and dissolving theingredients as appropriate to give the desired end product.

The method of producing dopaminergic activity in accordance with thisinvention comprises administering internally to a subject in need ofsuch activity a compound of Formula I or a pharmaceutically acceptableacid addition salt thereof, usually combined with a pharmaceuticalcarrier, in a nontoxic amount sufficient to produce said activity asdescribed above. The route of administration may be any route whicheffectively transports the active compound to the dopamine receptorswhich are to be stimulated such as orally or parenterally, the oralroute being preferred. Advantageously, equal doses will be administeredseveral times such as 2-5 times a day with the daily dosage regimenbeing selected from about 50 mg to about 2 g. When the method describedabove is carried out hypotensive, diuretic or antiparkinsonism activityis produced with a minimum of side effects. The O-diacyl derivatives mayowe their activity to the parent dihydroxy compound following metabolismin the body. Therefore any compound derived from those of Formula Iwhich owe activity to a parent compound or one of its metabolites isconsidered a part of this invention.

The following examples are designed solely to illustrate the preparationand use of the compounds of this invention. The temperatures areCentigrade. Other variations of these examples will be obvious to thoseskilled in the art.

EXAMPLE 1

A mixture of 100 g (0.55 mol) of 3,4-dimethoxyphenylethylamine and 66.2g (0.55 mol) of styrene oxide in 200 ml of tetrahydrofuran was refluxedovernight. The solvent was removed in vacuo. About 500 ml of n-butylchloride was added to the residue and the mixture cooled slightly.Filtration furnishedN-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenyl-2-hydroxyethylamine, m.p.92°-93°.

The above prepared phenethylamine, 71.5 g (0.238 mol), was dissolved in400 ml of acetic acid and the solution was cooled. To this solution wasadded 16.9 g (0.238 mol) of chlorine gas over a 30 to 45 minute period.The reaction mixture was poured into water, made basic with 40% sodiumhydroxide solution and about 250 ml of ether added to the stirredsolution. The resulting solid was filtered to giveN-[2-(2-chloro-4,5-dimethoxyphenyl)ethyl]-2-phenyl-2-hydroxyethylamine,m.p. 110°-113°.

To 100 ml of concentrated sulfuric acid was added the abovephenethylamine (10 g, 30 mmol) with stirring. After about 20 minutes thereaction mixture was poured over ice and extracted with ethyl acetate.The aqueous solution was made basic with sodium hydroxide pellets and40% sodium hydroxide solution. The oil which forms was extracted withether, the extract was dried and concentrated to about one-half volume.Ethereal hydrogen chloride was added to furnish6-chloro-8,9-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 209°-210°.

Heating the dimethoxy compound in an excess of 48% hydrobromic acid atreflux for 2 hours and cooling gives the 8,9-dihydroxy congener as thehydrobromide.

EXAMPLE 2

Isovanillin (200 g, 1.32 mole) was suspended in 1200 cc chloroform.Chlorine (103 g, 1.45 mole) was added by means of 3 500 cc portions ofcarbon tetrachloride, in which it was dissolved. The suspension wasstirred vigorously during the addition and the reaction was kept around25° by a water bath. The suspension was stirred for 22 minutes after thecompletion of the addition of chlorine. The precipitate was filtered andcrystallized from methanol, then recrystallized from isopropanol/ethylacetate. Yield 98.7 g (40%, m.p. 204°-206°) of2-chloro-3-hydroxy-4-methoxybenzaldehyde.

The aldehyde product (189.3 g, 1.02 mole) was suspended in 1 l. of drydimethylformamide, 350 g of potassium carbonate was added. 145 cc (124g, 1.54 mole) of dimethyl sulfate was added dropwise over a 20 minuteperiod. After the addition the reaction was heated on the steam bath for5 minutes. 70 cc of water were added and the reaction was again heatedfor 5 minutes on the steam bath. The mixture was then poured into icewater and the precipitate was collected. It was crystallized from aceticacid/water (800 cc-50 cc). A second crop was obtained from the motherliquor. Yield 180 g (90%) of 2-chloro-3,4-dimethoxybenzaldehyde afterdrying, m.p. 69°-70°.

The dimethoxybenzaldehyde (180 g, 0.9 mole) was dissolved in 500 cc warmacetic acid. 61 g (0.8 mole) of ammonium acetate was added, followed by160 cc of nitro-methane. The reaction was heated vigorously on the steambath for 3 hours. Water was then added to the cloud point, while stillheating, and the solution was cooled and scratched. The β-nitrostyrenebegan to oil out and then crystallized. The solution was cooled. Theyellow crystals were collected and dried in a vacuum oven. Yield 175 g(80% m.p. 88°-91°) of 2-chloro-3,4-dimethoxy-β-nitrostyrene.

The nitrostyrene (80 g, 0.33 mole) was dissolved in 800 cc of drytetrahydrofuran. Lithium aluminum hydride, as a 3.7 M solution (260 cc,0.36 mole), was put in a 5 1. 3 neck flask which has been dried andflushed with argon. It was diluted with 500 cc of dry ether. Thesolution of the nitrostyrene was added in a thin stream. The flask wascooled in an ice bath so that the heat of reaction caused a gentlereflux of the ether. After addition, the reaction was refluxed one hour,then worked up by adding 36 cc of water, 36 cc of 10% sodium hydroxideand 108 cc of water sequentially and carefully, while cooling thereaction in ice.

The precipitate was collected, washed well with ethyl ether anddiscarded. The ether-tetrahydrofuran mixture was evaporated.

The above reaction was repeated on 83 g of nitrostyrene. The two crudeproducts were combined and distilled at 0.5 mm to collect at 142°-155°the product containing fraction which was pure2-(2-chloro-3,4-dimethoxyphenyl)ethylamine by t.l.c. (80 g).

The phenethylamine (25.7 g, 0.12 mole) was heated to 115° in an oilbath. Styrene oxide (14.4 g, 0.12 mole) was added and the reaction washeated for 1 hour. After cooling to ˜30°, 2:1 petroleum ether/acetonewas added to dissolve the oil;N-[(2-hydroxy-2-phenylethyl)]-N-[2-(2'-chloro-3',4'-dimethoxyphenyl)ethyl]amine,crystallized out in 37% yield (15 g) m.p. 100°-101°.

The hydroxyphenethylamine (15 g, (0.445 mole) was dissolved in 60 cc oftrifluoroacetic acid and 4.05 cc of concentrated sulfuric acid wasadded. The reaction was refluxed 2 hours. After cooling most of thetrifluoroacetic acid was stripped off and the residue was poured intowater. It was made basic with 10% sodium hydroxide and was extractedwith ether twice. The ether was dried, and as it was evaporated, a solidseparated which was collected; m.p. 115°-121°, 6.0 g of6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Theremaining ether was treated with ethereal hydrogen chloride and thehydrochloride salt precipitated; yield 3.2 g, total 62% m.p. 234°-236°.The dimethoxy derivative was converted to6-chloro-7,8-dihydroxy-1phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide using boron tribromide in a 77% yield, m.p. 259°-260°.

EXAMPLE 3

7,8-Dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (280 g, 0.75mole) was dissolved in 1700 cc of acetic acid. Bromine (280 g, 1.75mole) was added in a thin stream. The reaction was stirred for twohours. The precipitate, which formed after 1 hour, was collected andwashed with ether. It was dissolved in boiling methanol and acetone wasadded to destroy the bromine excess.6-Bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide was allowed to crystallize from the methanol and a secondcrop was obtained by adding ether to the mother liquor. Yield 298 g, 77%m.p. 236-238%. This bromination may be applied to any 7,8-dialkoxy oralkanoyloxybenzazepine having a free 6-position.

The hydrobromide was shaken in a mixture of excess 10% sodium hydroxideand methylene chloride. The organic layer was separated, dried andevaporated to give a solid base which was crystallized fromtoluene-hexane; m.p. 125°-128°, yield 238 g (97%).

The base (12 g, 0.033 mole) was dissolved in 200 cc of methylenechloride and was cooled to -15° C. Boron tribromide (15.4 l cc, 16 mole)was added cautiously. The reaction was allowed to run at roomtemperature for two hours. The solvent was stripped off and the flaskwas cooled to -15°. Dry methanol was added to destroy the borontribromide complexes. It was then stripped off. The residue wascrystallized from water, then boiled in acetonitrile to aid in thedrying of the compound. Yield of6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide; 10.26 g (75%), m.p. 240°-242° after vacuum drying.

Other compounds having a free B 6-position and no interfering groupssuch as unsaturated or aromatic activating centers as known to the artmay be similarly brominated.

EXAMPLE 4

6-Bromo-7,8-dimethoxy-1-phenyltetrahydrobenzazepine (13 g, 0.0355 mole)was dissolved in 200 cc of dry acetone. Anhydrous potassium carbonate(10 g, 0.07 mole) was added, followed by 4.2 cc (0.0355 mole) of benzylbromide. The reaction was refluxed four hours. After cooling, the solidwas filtered and the filtrate was stripped off. The resulting oil wasdissolved in ether, filtered, and ethereal hydrogen chloride was added.The crystalline precipitate of N-benzyl derivative was filtered andrecrystallized from methanolether, m.p. 160°-165°.

The solid was then dissolved in methylene chloride and was extractedtwice with excess 10% sodium hydroxide. The solvent was dried andevaporated. The residue was dissolved in dry benzene and the benzene wasdistilled to azeotrope any water present. After repeating the procedure,the oil was pumped under vacuum to remove the benzene. Yield ofN-benzyl-6-bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine,12.5 g, 80%.

The 6-bromobenzyl derivative (12.5 g, 0.0277 mole) was converted to its6 -lithium salt which is an important intermediate by reaction withn-butyl lithium in ether. The n-butyl lithium (29 cc, 2.2 M, 0.064 mole)was added via syringe to a 3 neck flask in an organ atmosphere. It wasdiluted with 3 or 4 volumes of dry ether and cooled to -78° in a dryice-propanol bath. The benzyl compound was added in 75 cc of dry etherin a thin stream, over a five minute period. The reaction stirred at-78° for five minutes and then 13 g (0.0554 mole) of hexachloroethanewas added in 75 cc of ether. The precipitate dissolved immediately.

The reaction mixture was poured into water and the ether layer wasretained. The water was extracted again with ether and the ether wasdried with magnesium sulfate. Addition of ethereal hydrogen chloridegave a precipitate which was crystallized first from ether-methanol,then from ethyl acetate. Yield of3-benzyl-6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, 9.4 g (80%), m.p. 201°-205°.

This N-benzyl compound (B 5.33 g, 0.013 mole) was freed from itshydrochloride by extraction into methylene chloride after makingalkaline a solution of the hydrochloride. The methylene chloride wasdried, evaporated, and the residue dissolved in benzene. It was strippeddown to azeotrope any water remaining and the residue was dissolved in50 cc of dry benzene.

Cyanogen bromide (1.53 g, 0.0144 mole) was dissolved in 50 cc of drybenzene and was warmed to 55°. The N-benzyl compound was added dropwisein benzene and the mixture stirred for 3 hours. The volatiles werestripped off, leaving a solid which was triturated with ether. Yield ofN-cyano derivative; 4.0 g (89%, m.p. 149°-151°.

This material (4.0 g, 0.127 mole) was dissolved in a solution of 55 ccof acetic acid, 6 cc of conc. hydrochloric acid and 31 cc of water. Itwas heated overnight on the steam bath. The solvents were then strippedoff and the residue dissolved in hot methanol. Ether was added and6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride crystallized; yield 3.85 g (90%), m.p. 241°-245°.

EXAMPLE 5

The product of Example 4 (3.27 g, 0.0103 mole) was freed from itshydrochloride by making basic its aqueous solution and extracting themixture with methylene chloride. The solvent was carefully dried andcooled to -15° by a methanol-ice bath. Boron tribromide (4 cc) was addedand the reaction was stirred at room temperature for 2 hours. Thesolvent and excess tribromide were stripped and the flask cooled to-78°. Methanol was added cautiously until all the material wasdissolved. The methanol was stripped off and the residue crystallizedfrom hot water. The crystals were boiled in dry acetonitrile for anhour, then collected to give6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide; (56%), m.p. 256°-260°.

EXAMPLE 6

2-Chloro-3,4-dimethoxyphenethylamine (1.0 g) was reacted with 0.70 g ofo-methylstyrene oxide as described above to give thehydroxyphenethylamine. This compound (2.16 g) was stirred at roomtemperature in 15 ml of trifluoroacetic acid with 4 drops of conc.sulfuric acid. Working up as above gave, after purification over asilica gel column with chloroform, 10% methanol/chloroform as eluates,the desired6-chloro-7,8-dimethoxy-1-o-methylphenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.This after demethylation gave the 6-chloro-o-methylphenyl, m.p.233°≠236° (HBr salt).

EXAMPLE 7

A mixture of 42.0 g of 57% sodium hydroxide dispersed in oil and 70 mlof dimethyl sulfoxide is stirred at 70°-75° for one to one and one-halfhours. The solution is diluted with 700 ml of dry tetrahydrofuran andcooled to 0°, under nitrogen. A 200 g of (1.0 mol) sample oftrimethylsulfonium iodide is added in portions, maintaining thetemperature between 0°-5°. The mixture is stirred for 15 minutes andthen a solution of 70.4 g (0.50 mol) of o-chlorobenzaldehyde in 300 mlof dry tetrahydrofuran is added dropwise. The resulting mixture isstirred at room temperature for four hours, poured into water andextracted with ether. The extract is washed with brine, dired andevaporated in vacuo to leave o-chlorostyrene oxide.

A solution of 27.5 g of N-benzyl-2-chloro-3,4-dimethoxyphenylethylamineand 23.3 g (0.15 mol) of m-chlorostyrene oxide in 500 ml of methanol isstirred and refluxed overnight. The methanol is removed in vacuo and theresidualN-benzyl-N-[2-(2-chloro-3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-chlorophenyl)ethylamineis reduced without further purification. This sample (0.01 mol) isdissolved in ether, acidified with ethereal hydrogen chloride and thehydrochloride precipitates. The latter is dissolved in 90 ml ofmethanol, the solution is added to a mixture of 0.5 g ofpalladium-on-charcoal in 10 ml of ethyl acetate and the mixture ishydrogenated at room temperature for 90 minutes at 60 psi. The reactionmixture is filtered and the filtrate evaporated in vacuo to yieldN-[2-(2-chloro-3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-chlorophenyl)ethylaminehydrochloride.

A solution of 6.0 g (0.0161 mol) of the above prepared compound in 250ml of 48% hydrobromic acid is stirred and refluxed for three hours. Thereaction mixture is evaporated in vacuo to give6-chloro-1-(2-chlorophenyl)-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

EXAMPLE 8

Following the procedure of Example 7 and employing 42.0 g of 57% ofsodium hydride in mineral oil, 200 g (0.1 mol) of trimethylsulfoniumiodide and 70.4 g (0.50 mol) of o-bromo-benzaldehyde there is obtainedo-bromostyrene oxide.

Similarly 2.71 g of N-benzyl-2-chloro-3,4-dimethoxyphenethylamine and2.33 g (0.015 mol) of o-bromostyrene oxide are reacted in methanol togiveN-benzyl-N-[2-(2-chloro-3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-bromophenyl)ethylamine.The latter is converted to its hydrochloride, which is dissolved in 90ml of methanol and hydrogenated over 1 g of 10% palladium-on-carbon in10 ml of ethyl acetate at room temperature for six hours. The reactionmixture is filtered and evaporated in vacuo to leaveN-[2-(2-chloro-3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-bromophenyl)ethylaminehydrochloride.

A solution of 4.0 g of the above hydrochloride in 250 ml of 48%hydrobromic acid is stirred and refluxed for two hours. The reactionmixture is evaporated in vacuo to yield6-chloro-1-(2-bromophenyl)-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

Substituting trifluoromethyl, fluoro, methyl, ethyl, ethoxystyreneoxides will give the compounds of this invention whose structuresinclude the corresponding substituted 1-phenyl moieties.

EXAMPLE 9

A 4.0 g sample of3-benzyl-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(prepared from the 3-unsubstituted benzazepine by reaction with benzylbromide in the presence of potassium carbonate) is dissolved in 50 ml ofacetic anhydride and the solution is heated on a steam bath for onehour. The reaction mixture is cooled, ice-water is added and thesolution is evaporated to dryness. The residue is triturated with ethylacetate, the solution washed with water, dried and the solvent removedin vacuo to leave an oil. The latter is dissolved in ether and etherealhydrogen chloride is added to precipitate3-benzyl-6-chloro-7,8-diacetoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride.

The diacetoxy compound prepared above, 3.5 g is dissolved in 100 ml ofethanol and 1 g of 10% palladium-on-carbon is added. The mixture ishydrogenated in a Parr apparatus at 50° under 50 psi of hydrogen for onehour. The reaction mixture is filtered and the filtrate is evaporated togive 6-chloro-7,8-diacetoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride. This compound has a melting point of 234°-235°.

Alternatively6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide (10 g) is dissolved in trifluoroacetic acid and reactedwith a stoichiometric amount of acetyl chloride at room temperature. Thenext day the reaction mixture is evaporated and the residuerecrystallized to give the desired diacetoxy derivative.

Substituting other alkanoyl anhydrides or chlorides gives various7,8-alkanoyl derivatives.

EXAMPLE 10

Substituting a stoichiometric quantity of2-fluoro-3,4-dimethoxyphenethyl amine in the synthetic procedures abovegives 6-fluoro-7,81-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Hydrolysis withboron tribromide as in Example 2 gives6-fluoro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.This compound as the hydrobromide has a melting point of 271° (dec.).Substituting 2-trifluoromethyl-3,4-dimethoxytoluene, in Example 2 gives6-trifluoromethyl-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinethen hydrolysis with boron tribromide gives6-trifluoromethyl-7,8-dihydroxy-1-phenyl-3,4,5-tetrahydro-1H-3-benzazepine.This compound as the hydrochloride has a melting point of 155°.

EXAMPLE 11

A mixture of 4.84 g of 50% of sodium hydride in mineral oil and 70 ml ofdry dimethylsulfoxide was stirred at 65°-70° for 80 minutes. Afterdilution with 70 ml of dry tetrahydrofuran, the mixture was cooled to 0°while a solution of 19.0 g (0.093 mole) of trimethylsulfonium iodide in100 ml of dimethylsulfoxide was added. A solution of 12.6 g (0.0928mole) of m-anisaldehyde in 40 ml of tetrahydrofuran was quickly added.After stirring for 15 minutes at 0° and 11/2 hour at 25°, the mixture ispoured into 11/2 l. of ice/water slurry and extracted well with water.The combined organic layers were washed with brine, dried andconcentrated to give 13 g of crude epoxide. This is mixed with 13.0 g of2-(2-chloro-3,4-dimethoxyphenyl)ethylamine and heated at 110° for 4hours. The product was chromatographed over silica gel with 3%methanol/chloroform. The product containing cuts were worked up to give1.9 g ofN-[2-(2-chloro-3,4-dimethoxyphenyl)-ethyl]-2-hydroxy-2-(m-methoxyphenyl)ethylamine,m.p. 95.5°-96.5°.

The p-chlorophenyl congener melted at 99°-100°. The p-methylphenylcongener melted at 117°-118°.

The m-methoxy substituted hydroxyphenethylamine intermediate (1.7 g) in25 ml of 48% hydrogen bromide solution was cyclized in trifluoroaceticacid-sulfuric acid as described above;6-chloro-7,8-dimethoxy-1-(m-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

The p-chlorophenyl-7,8-dihydroxy congener melted at B 243°-246°. Thep-methylphenyl-7,8-dihydroxy congener melted at 250°-253°.

EXAMPLE 12

A mixture of 8.0 g of 2-chloro-3,4-dimethoxy-phenylamine and 5.25 g ofm-trifluoromethyl-α-methoxy-phenethylbromide is heated at 100°-105° for21/2 hours. The product was partitioned between ethyl acetate and 5%sodium bicarbonate solution. The organic layer was removed, washed withbrine, dried and concentrated. The residue was passed over 350 g ofsilica gel with 1 to 2% methanol/chloroform. The resulting product wasan oil whose hydrochloride melted at 200°-202°. The oily base (2.5 g)was heated with 50 ml of 48% hydrogen bromide and worked up as above togive the desired6-chloro-7,8-dihydroxy-1-(m-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. ˜250°.

6-Bromo-7,8-dimethoxy-1-phenyl-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine(5 g, prepared by reaction of trifluoroacetic anhydride in benzene onthe N-hydrogen compound) is reacted with an excess of butyl lithium inether to give the 6-lithium salt-3-butyl-lithium adduct. Thisintermediate is reacted without isolation with iodine. After hydrolysiswith water,6-iodo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine isobtained. This compound is treated with boron tribromide as describedabove to give the 7,8-dihydroxy derivative.

2-Chloro-3-hydroxy-4-methoxybenzaldehyde is treated with hydrogenbromide to give 2-chloro-3,4-dihydroxybenzaldehyde which is converted tothe methylenedioxy derivative with dibromoethane as described above. Theproduct is condensed with nitromethane and the resulting nitroethylenereduced to give the phenethylamine. This compound is condensed withp-methoxystyrene oxide to give the α-hydroxyphenethylamine intermediatewhich is treated with an excess of trifluoroacetic acid at roomtemperature for 18 hours to give6-chloro-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.This compound is split using boron trichloride as described above togive6-chloro-7,8-dihydroxy-1-p-methoxyphenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

EXAMPLE 13

A solution of 0.74 g (0.002 mole) of6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, 0.55 g (0.0025 mole) of p-trifluoromethylbenzoylchloride, 0.17 g (0.002 mole) of sodium bicarbonate and 40 ml of1:1 acetone-water solution was stirred overnight under nitrogen. Themixture was evaporated to dryness. The residue was extracted withethylacetate. The extracted material was purified over a silica gelcolumn using methanol-ethyl acetate to give6-chloro-7,8-dihydroxy-1-phenyl-3-(p-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-3-benzazepine,m.p. 243°-245° (dec.).

This compound (1.65 g, 0.00357 mole) in 120 ml of tetrahydrofuran wasadded to 15 ml of 1 M boron hydridetetrahydrofuran. After heating atreflux for 2 hours methanol was added with 10 ml of 6 N hydrochloricacid. The solution was evaporated to give a white solid which wasdissolved in 50 ml of 6 N hydrochloric acid, heated at reflux for 1 hourand again evaporated. The white solid was purified from methanolethylacetate-ether to give6-chloro-7,8-dihydroxy-1-phenyl-3-(p-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 239°-241° (dec.).

EXAMPLE 14

Using methods described here in the following compounds were prepared:

6-chloro-7,8-dimethoxy-1-phenyl-3-α-thenoyl-2,3,4,5-tetrahydro-1H-3-benzazepine,yellow liquid

6-chloro-7,8-dihydroxy-1phenyl-3-α-thenoyl-2,3,4,5-tetrahydro-1H-3-benzazepine,green solid

6-chloro-7,8-dihydroxy-1-phenyl-3-α-thenyl-2,3,4,5-tetrahydro-1H-benzazepinehydrochloride, m.p. 237°-240°

6-chloro-7,8-dimethoxy-3-α-furoyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine,yellow liquid

6-chloro-7,8-dihydroxy-3-α-furoyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine,brown solid

6-chloro-7,8-dihydroxy-3-α-furylmethyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 239°-240°

6-chloro-1-(p-chloro-m-hydroxyphenyl)-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 270°-273°

6-chloro-1-(m,m-dichloro-p-hydroxyphenyl)-7,8-dihyroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 290°-292°

6-chloro-1-(m-chlorophenyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 160°-163°

6-chloro-1-(m-chlorophenyl)-7,8-dihydroxy-3-α-furylmethyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 241°-243°

6-chloro-1-(m-chlorophenyl)-7,8-dihyroxy-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 273°-275°

6-chloro-7,8-dimethoxy-1-(m-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 136°-140°

6-chloro-7,8-dihydroxy-1-(m-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 120°-123°

6-chloro-7,8-dimethoxy-3-α-furylmethyl-1-(m-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 235°-237°

6-chloro-7,8-dihydroxy-3-α-furylmethyl-1-(m-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 262°-265°

6-chloro-7,8-dihydroxy-1-(o-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 233°-236°

6-chloro-7,8-diacetoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 234°-235°

6-chloro-7,8-dihydroxy-1-(m-chloro-p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 295°

6-bromo-7,8-diacetoxy-1-(m-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide, m.p. 224°.

Many of the compounds of the series exist in the salt form as solvatessuch as hydrates.

EXAMPLE 15

    ______________________________________                                        Ingredients           Mg. per Capsule                                         ______________________________________                                        6-Chloro-7,8-dihydroxy-1-phenyl-                                                                    125 (free base)                                         2,3,4,5-tetrahydro-1H-3-benzazepine                                           (as an acid addition salt)                                                    Magnesium stearate    2                                                       Lactose               200                                                     ______________________________________                                    

The above ingredients are thoroughly mixed and placed into hard gelatincapsules. Such capsules are administered orally to subjects in need oftreatment from 2-5 times daily to induce dopaminergic activity.

EXAMPLE 16

    ______________________________________                                        Ingredients           Mg. per Tablet                                          ______________________________________                                        6-Chloro-7,8-dihydroxys-1-phenyl-                                                                   200 (free base)                                         2,3,4,5-tetrahydro-1H-3-benzazepine                                           (as an acid addition salt)                                                    Corn starch           30                                                      Polyvinyl pyrrolidone 12                                                      Corn starch           16                                                      Magnesium stearate    3                                                       ______________________________________                                    

The first two ingredients are thoroughly mixed and granulated. Thegranules obtained are dried, mixed with the remaining corn starch andmagnesium stearate, and compressed into scored tablets.

The capsules or tablets thusly prepared are administered orally to ananimal or human requiring stimulation of either central or peripheraldopamine receptors within the dose ranges set forth hereinabove.Similarly other compounds of Formula I and the illustrative examples canbe formulated in the same manner to give pharmaceutical compositionsuseful in the methods of this invention based on their chemicalcharacteristics and their relative biological activity using the testmethods outlined.

What is claimed is:
 1. A compound of the formula: ##STR5## in which: Ris hydrogen;R₁ is halo or trifluoromethyl; R₂ and R₃ are hydrogen orlower alkanoyl of from 2-7 carbons; and R₄ is hydrogen, trifluoromethyl,halo, methyl or methoxy;together with its nontoxic, pharmaceuticallyacceptable salts.
 2. A compound of claim 1 in which R and R₄ arehydrogen and R₁ is chloro.
 3. A compound of claim 1 in which R₄ ishydrogen.
 4. A compound of claim 1 in which R₁ is chloro.
 5. A compoundof claim 1 in which R₂ and R₃ are hydrogen.
 6. The compound of claim 1being6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, itshydrohalide or methane sulfonate salts.
 7. The compound of claim 1 being6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, itshydrohalide or methane sulfonate salts.
 8. The compound of claim 1 being6-chloro-7,8-diacetoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, itshydrohalide or methane sulfonate salts.
 9. The method of producingdopaminergic activity in a subject in need thereof comprisingadministering orally or by injection an effective quantity of a compoundof claims 1, 4 or 6 which is nontoxic and dopaminergic.
 10. Thepharmaceutical composition having dopaminergic activity comprising anontoxic dopaminergic quantity of a compound of claims 1, 4 or 6 whichis selected from the range of 15-1000 mg. of compound per dosage unit.11. The composition of claim 10 in which the dosage unit is adapted fororal use selected from the range of 25-300 mg.